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Participants who either do not have cancer but are at high risk for developing the disease or have had cancer and are at high risk for developing a new cancer.

Healthy Volunteer

By Study Information

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These trials look at ways to improve the quality of life of cancer patients, especially those who have side effects from cancer and its treatment. They find new ways to help people cope with pain, nutrition problems, infection, nausea and vomiting, sleep disorders, depression and other health problems.

open for enrollment

Inclusion Criteria:
- New onset high risk acute GVHD (Ann Arbor score 3 as defined in Appendix C of the
protocol) following allogeneic bone marrow transplantation. Any clinical severity
(Glucksberg grade I-IV) is eligible.
- Any donor type (e.g., related, unrelated) or stem cell source (bone marrow,
peripheral blood, cord blood). Recipients of non-myeloablative and myeloablative
transplants are eligible.
- No prior systemic treatment for acute GVHD except for a maximum of 72 hours of
prednisone ≤2 mg/kg/day (or IV methylprednisolone equivalent). Topical skin steroid
treatment is permissible. Non-absorbable oral steroid treatment for GI GVHD is
prohibited.
- Age 12 years or older.
- If the patient is a woman of child-bearing potential, the patient and their sexual
partner must agree to practice effective contraception.
- Written informed consent from patient, parent, or guardian.
- Written assent from patients age 12 to 17 years.
- Biopsy of acute GVHD target organ is strongly recommended, but not required.
Enrollment should not be delayed for biopsy or pathology results. Patients who do not
enroll within 72 hours of new onset acute GVHD are not permitted to participate.
Exclusion Criteria:
- Progressive or relapsed malignancy
- Uncontrolled active infection
- Patients with chronic GVHD
- Known seropositivity for JC virus
- History of Progressive Multifocal Leukoencephalopathy (PML)
- Known hypersensitivity to natalizumab
- Pregnant or nursing (lactating) women
- Use of other drugs for the treatment of acute GVHD
- Patients on dialysis
- Patients requiring ventilator support
- Investigational agent within 30 days of enrollment without approval from the
Sponsor-Investigator

Female patients must be surgically sterile, post-menopausal (for at least 1 year), or have negative results from a pregnancy test performed as follows:

At screening, on a serum sample obtained within 14 days prior to the first study drug administration, and

Prior to dosing, on a urine sample obtained on day 1 of treatment if it has been > 7 days since obtaining the serum pregnancy test result

All female patients not surgically sterile or post-menopausal (for at least 1 year) and non-vasectomized male patients must practice at least one of the following methods of birth control:

Total abstinence from sexual intercourse (minimum one complete menstrual cycle)

A vasectomized partner

Hormonal contraceptives for at least 2 months prior to day 1 of treatment

Double-barrier method

Non-vasectomized male patients must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 3 months after study treatment:

A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at least 3 months prior to study drug administration

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

Patients who have had chemotherapy, immunotherapy, radiotherapy, or investigational therapy within 28 days prior to entering the study or those who have not recovered from adverse events due to agents administered more than 28 days earlier; steroids for control of disease related symptoms are permitted

Patients who are receiving any other investigational agents

Uncontrolled autoimmune hemolytic anemia or thrombocytopenia

Active Richter’s transformation

Known active involvement of the central nervous system by lymphoma or leukemia

Patients who require warfarin anticoagulation or who have received warfarin or equivalent vitamin K antagonists =< 7 days prior to treatment day 1; patients may be eligible if able to be taken off warfarin and started on an alternative anticoagulant

Received potent cytochrome P450 3A4 (CYP3A4) inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of study treatment

Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St. John’s wort) within 7 days prior to the first dose of study treatment

Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study treatment

History of a prior significant toxicity, other than thrombocytopenia, from another Bcl-2 family protein inhibitor

Known cysteine-481 Bruton's tyrosine kinase (BTK) mutation or CLL refractory to or progressed during ibrutinib or other cysteine (Cys)-481 binding BTK inhibitor treatment

Known infection with the human immunodeficiency virus (HIV) virus

A cardiovascular disability status of New York Heart Association class >= 2, defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain

Positive hepatitis serology:

Hepatitis B virus (HBV): patients with positive serology for hepatitis B defined as positivity for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc); patients who are positive for anti-HBc may be considered for inclusion in the study on a case-by-case basis if they are hepatitis B viral deoxyribonucleic acid (DNA) negative and are willing to undergo ongoing HBV DNA testing by real-time polymerase chain reaction (PCR); patients with positive serology may be referred to a hepatologist or gastroenterologist for appropriate monitoring and management

Patients suspected to have false positive serologic studies because of IV immunoglobulin administration are potentially eligible after negative PCR studies for viral DNA/ribonucleic acid (RNA) and discussion with the principal investigator

Hepatitis C (HCV): patients with positive hepatitis C serology unless HCV RNA is confirmed negative and may be considered for inclusion in the study on a case-by-case basis (e.g., patients with negative viral load after HCV-specific treatment)

Diagnostic bone marrow and peripheral blood specimens must be submitted for immunophenotyping and selected molecular testing, and the establishment of BCR/ABL status; testing will be performed by the Eastern Cooperative Oncology Group (ECOG)-American College of Radiation Imaging Network (ACRIN) Leukemia Translational Research Laboratory (LTRL) and reported to the institution

NOTE: IT IS ESSENTIAL THAT A SAMPLE CONTAINING SUFFICIENT BLAST CELLS BE SUBMITTED TO THE ECOG-ACRIN LTRL AT BASELINE SO THAT SUBSEQUENT BONE MARROW ASSESSMENTS OF MRD CAN BE DONE; IN ADDITION TO ALLOWING THE LTRL TO CONFIRM ELIGIBILITY BASED ON BLAST CELL IMMUNOPHENOTYPE AND BCR/ABL STATUS, IT IS ALSO IMPERATIVE THAT AN ADEQUATE NUMBER OF BLASTS BE BANKED FOR ANALYSIS BY DRS MULLIGHAN/WILLMAN. WITHOUT ADEQUATE BASELINE SAMPLES, PATIENTS WILL NOT BE ABLE TO BE TREATED AND RANDOMIZED ON THIS PROTOCOL; IF A BONE MARROW ASPIRATE IS NOT AVAILABLE FOR LTRL SUBMISSION AT BASELINE, IT IS IMPERATIVE THAT DR PAIETTA FROM THE LTRL IS CALLED TO DISCUSS THE PERIPHERAL BLOOD WBC AND BLAST COUNT BEFORE BLOOD ONLY IS SUBMITTED

INDUCTION ELIGIBILITY CRITERIA-STEP 1

New diagnosis of B lineage ALL must be made upon bone marrow or peripheral blood immunophenotyping; cases with myeloid antigen expression, but unequivocal lymphoid immunophenotype, are eligible

Mature B ALL (Burkitt’s-like leukemia) is excluded from enrollment in this trial

Negativity for the Philadelphia chromosome must be established by conventional cytogenetics, fluorescence in situ hybridization (FISH) and/or polymerase chain reaction (PCR); patients who are negative for the Philadelphia chromosome by conventional cytogenetics must have FISH or PCR performed for BCR/ABL to exclude occult translocations

Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if adequate number of circulating blasts from peripheral blood; FISH testing for common B-lineage ALL abnormalities including t(9;22) (BCR/ABL1), t(12;21) (ETS-variant gene 6 [ETV6]/runt-related transcription factor 1 [RUNX1]), t(1;19) (pre-B-cell leukemia homeobox 1 [PBX1]/transcription factor 3 [TCF3]), +4,+10,+17, (centromeric [Cen]4/Cen10/Cen17), t(11q23;var), (myeloid/lymphoid or mixed lineage leukemia [MLL]), deletion (del)(9p) (cyclin-dependent kinase inhibitor 2A [CDKN2A]/Cen9), and t(14;var) (immunoglobulin heavy chain [IGH] is encouraged); if there are few or no circulating blasts and an adequate marrow sample cannot be obtained for cytogenetic analysis, the patient may still enroll on the trial

Patient must not have a concurrent active malignancy for which they are receiving treatment

Serum direct bilirubin < 2 mg/dl or serum total bilirubin =< 3; NOTE: the above stipulation for normal hepatic function does not apply if liver dysfunction is due to leukemia infiltration

Serum creatinine < 2 mg/dl; NOTE: the above stipulation for normal hepatic function does not apply if liver dysfunction is due to leukemia infiltration

Patient should be human leukocyte antigen (HLA) typed (A, B, C, DR and DQ) during induction therapy phase or a written explanation for not undergoing HLA typing on the flow sheet

Patient must not have intercurrent organ damage or medical problems that will jeopardize the outcome of therapy (i.e., psychiatric disorder, drug abuse, pregnancy)

Patients with known human immunodeficiency virus (HIV) infections are not eligible

Patient must not have an antecedent hematologic disorder

Patient must have no history of recent myocardial infarction (within three months), uncontrolled congestive heart failure, or uncontrolled cardiac arrhythmia

Patient must not have a history or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia; Parkinson’s disease, cerebellar disease, organic brain syndrome, psychosis, or other significant CNS abnormalities

Patient must have a normal cardiac ejection fraction by pretreatment multigated acquisition scan (MUGA) or echocardiogram within 4 weeks prior to registration (resting ejection fraction >= 40% or >= 5% increase with exercise), shortening fraction by echocardiogram >= 24%, or to within the normal range of values for the institution

Patient must not have an active uncontrolled infection

Women must not be pregnant or breast-feeding and must not become pregnant or breastfeed during protocol therapy and for at least 3 months after protocol therapy; woman of childbearing potential must abstain from sexual activity or be willing to use 2 highly effective forms of contraception throughout protocol therapy and for at least an additional 3 months after the last dose of protocol-specified therapy; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Men who have a female partner of childbearing potential must be willing to use 2 highly effective forms of contraception throughout protocol therapy and for at least an additional 3 months after the last dose of protocol-specified therapy; men who have a pregnant partner must be willing to use a condom during sexual activity throughout protocol therapy and for 3 months after the last dose of protocol-specified therapy

Bone marrow aspirates must be submitted for centralized minimal residual disease (MRD) assessment performed by the ECOG-ACRIN Leukemia Translational Research Laboratory

MRD results will be reported to the submitting institution

NOTE: FOR MRD ASSESSMENTS, AN ASPIRATE FROM A SEPARATE BONE MARROW ASPIRATION SITE MUST BE SUBMITTED (THE NEEDLE CAN BE RE-DIRECTED THROUGH THE SAME SKIN PUNCTURE SITE); ONLY SUBMIT ASPIRATES FROM THE FIRST PULL OF AN ASPIRATION SITE FOR MRD TESTING; DO NOT SUBMIT SAMPLES FROM THE SECOND OR THIRD PULL OF THE SAME ASPIRATION SITE

In B-lineage ALL, MRD levels in peripheral blood or from a dilute marrow aspiration can be 300% lower, on average, than those in bone marrow at a given time point; submitting a first pull from a separate aspiration site will ensure that MRD determinations used in randomization and trial interpretation are accurate

NOTE: failure to submit bone marrow aspirates will result in a major violation at the time of an audit

CRITERIA FOR ALLOGENEIC TRANSPLANTATION

A suitable donor must be identified; there are no restrictions on donor type and can include a matched sibling, a matched or mismatched unrelated donor, a family haplotype matched donor or a cord blood donor (single or double)

Patients should meet the eligibility criteria for RANDOMIZATION TO BLINATUMOMAB OR NO BLINATUMOMAB-STEP 3

Patients must be considered reliable enough to comply with the medication regimen and follow-up, and have social support necessary to allow this compliance

CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have an ECOG performance status of 0-3

CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have maintained peripheral blood evidence of a remission and must have a CR or CRi, confirmed on restaging BM aspirate and biopsy and cytogenetic analysis

CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have resolved any serious infectious complications related to therapy

CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Any significant medical complications related to therapy must have resolved